mRNA-based vaccines against SARS-CoV-2 do not stimulate interferon stimulatory gene expression in individuals affected by Aicardi Goutières Syndrome

  1. Asako Takanohashi
  2. Mohamad-Gabriel Alameh
  3. Sarah Woidill
  4. Julia Hacker
  5. Benjamin Davis
  6. Guy Helman
  7. Francesco Gavazzi
  8. Laura Adang
  9. Russell D’Aiello
  10. Patrick Winters
  11. Devon Cordova
  12. Taibeen Khandaker
  13. Houping Ni
  14. Ying Tam
  15. Paulo Lin
  16. Drew Weissman
  17. Justine Shults
  18. Adeline Vanderver

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Abstract

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses threats to individuals with rare disease, in part because so little is known about the impact of COVID-19 infection and vaccination safety in rare disease populations. Of particular concern, given the overlap in disease manifestations and interferon dysregulation, are a group of heritable autoinflammatory conditions called type I interferonopathies. The most common of these, Aicardi Goutières Syndrome (AGS), is caused by altered nucleic acid metabolism and sensing, resulting in additional concerns surrounding the use of mRNA vaccination approaches. To determine whether mRNA vaccines induce an interferon response in AGS, we applied mRNA SARS-CoV-2 vaccines to whole blood samples and assessed internalization and interferon signaling gene expression responses to the mRNA. In all cases (11 AGS and 11 control samples), interferon signatures did not significantly increase from baseline, regardless of baricitinib treatment status in the AGS subjects, and were even decreased, when using codon optimized SARS-CoV-2 di-proline modified spike sequence (S2P). Internalization of S2P in human dendritic cells was verified by Western Blot, and in control and AGS blood cells was verified by Luciferase activity. Although numbers of tested samples in this rare disease are small, based on these findings, we suggest that COVID vaccination is unlikely to directly stimulate the interferon signaling gene expression in AGS patients via response to mRNA internalization. The in vitro nature of this study cannot exclude an exaggerated interferon response to spike protein production at a systemic level in individuals with a primary heritable interferonopathy. In the context of continued SARS-CoV-2 spread in the community, we do not recommend withholding vaccination in this rare disease group. However, we recommend that vaccinations for AGS patients are provided in a controlled setting with appropriate observation and used with caution in individuals with prior vaccine associated adverse events.

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  1. ScreenIT

    SciScore for 10.1101/2022.05.18.492546: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    Cells were washed once and incubated with a PE-labelled goat anti-human IgG secondary antibody (Thermo Fisher Scientific 12-4998-92) at a final concentration of 2.5μg/mL of 30 minutes at 4°C.
    anti-human IgG
    suggested: None
    Membranes were blocked in 5% non-fat milk for 1 hour, washed twice with TBS-T, incubated with rabbit anti-SARS-2-S at 1:2000 (Sino Biological 40591-T62) in 1% non-fat dry milk for 1 hour, washed twice in TBS-T and incubated in the presence of a goat HRP conjugated anti-rabbit secondary IgG antibody (1:10000; Abcam 6721).
    anti-SARS-2-S
    suggested: None
    HRP conjugated anti-rabbit secondary IgG
    suggested: (Abcam Cat# ab6721, RRID:AB_955447)
    Membranes were stripped and re-blotted in the presence of an anti-GAPH antibody as a loading control.
    anti-GAPH
    suggested: None
    Software and Algorithms
    SentencesResources
    Flow cytometric data was acquired using an LSRII and data analyzed using FlowJo 10.2.
    FlowJo
    suggested: (FlowJo, RRID:SCR_008520)
    A heatmap was generated using GraphPad Prism (GraphPad Software, San Diego, CA).
    GraphPad Prism
    suggested: (GraphPad Prism, RRID:SCR_002798)
    GraphPad
    suggested: (GraphPad Prism, RRID:SCR_002798)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

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  2. Version published to 10.1101/2022.05.18.492546v1 on bioRxiv